Carbonyl compounds acetoacetic ester synthesis

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

As was the case in the decarboxylation that occurs in the acetoacetic ester synthesis, it is the presence of a carbonyl group at the /3-position of the carboxylic acid that allows carbon dioxide to be lost when the compound is heated. 

Both the malonic ester synthesis and the acetoacetic ester synthesis arc relatively easy to carry out because they involve unusually acidic carbonyl compounds. As a result, relatively mild bases like sodium ethoxide in an alcohol solvent can be used to prepare the necessary enolate ions. Alternatively, it s also possible in many cases to alkylate the a position of monoketones, monoesters, and nitrile. . A strong, sterically hindered base such as LDA is needed, so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

In contrast, /3-dicarbonyl compounds such as malonic ester and acetoacetic ester are more acidic than alcohols. They are completely deprotonated by alkoxides, and the resulting enolates are easily alkylated and acylated. At the end of the synthesis, one of the carbonyl groups can be removed by decarboxylation, leaving a compound that is difficult or impossible to make by direct alkylation or acylation of a simple ester. 

The Hantzsch pyridine synthesis affords 1,4-dihydropyridines 214, although spontaneous oxidation to pyridines often occurs. In its simplest form it involves the condensation of two molecules of a -keto ester with an aldehyde and ammonia (Scheme 119) . Compounds resulting from the condensation of ammonia with one of the carbonyl components can be used in the Hantzsch synthesis. Thus, -aminocrotonic ester 215 can replace the ammonia and one mole of acetoacetic ester in Scheme 119. The mechanism of the Hantzsch synthesis has been clarified by 13C and 1SN NMR spectroscopy <1987T5171>. 

Vinyllithiums of type 663 (R2 = R3 = H) reacted with primary alkyl bromides, carbonyl compounds, carbon dioxide, DMF, silyl chlorides, stannyl chlorides, disulfides and phenylselenyl bromide142,970-979. Scheme 173 shows the synthesis of dihydrojasmone 669 from the corresponding 1,4-diketone. a-(Phenylsulfanyl)vinyllithium 665, prepared from phenyl vinyl thioether, reacted with hexanal and the corresponding adduct 666 was transformed into its acetoacetate. This ester 667 underwent a Carrol reaction to produce the ketone 668, which was transformed into the cyclopentenone 669 by deprotection either... 

Other carbonyl compounds carrying a second functional group undergo this reaction, e.g., acrolein, chloroacetone, -hydroxybenzaldehyde, acetoacetic ester, and -dimethylaminobenzaldehyde. The method is important in the synthesis of sugars (Kiliani cyanohydrin synthesis). ... 

This widely used general approach to pyrroles utilizes two components one, the a-aminocarbonyl component, supplies the nitrogen and C-2 and C-3, and the second component supplies the remaining two carbons and must possess a methylene group a to a carbonyl. The Knorr synthesis works well only if the methylene group of the second component is further acidified (e.g. as in acetoacetic ester, i.e. it is a 1,3-dicarbonyl compound, or equivalent) to enable the desired condensation leading to pyrrole to compete effectively with the self-condensation of the a-aminocarbonyl component. The synthesis of... 

One of the classical methods for the synthesis of pyrazines involves dimerization of an a-amino carbonyl compound and subsequent aromatization. Oximes have often been used as the latent functionality to generate the amine by a variety of reductive processes. 3-Oxo-2-oximinobutanoic esters or the amides (146), which are formed by nitrosation of acetoacetic acid derivatives, are reduced by catalytic hydrogenation <82CPB3424, 91JHC1731> or titanium(III)-induced reduction <88H(27)il23> to give the tetrasubstituted pyrazines (147) (Equation (17)). 

Another indole synthesis which corresponds to the Ic pattern is the reaction of anilines with a-halomethyl carbonyl compounds. The reactions of IV-alkylanilines with y-bromo or y-chloro-acetoacetate esters gives indoles in fair to good yields. This method can be applied to indole-3-acetate esters and amides and can incorporate branching in the acetate side-chain (Equation (25)) <62BSF1056, 64BSF1939). 

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